The present invention relates to new pharmacologically active imidazole derivatives and pharmaceutically acceptable salts and esters thereof, as well as to processes for their preparation and to pharmaceutical compositions containing them.
It is known that several derivatives of imidazole have affinity for alpha1 and/or alpha2 adrenoceptors. Accordingly, WO-A-97 12874 describes imidazole-substituted (1,2,3,4-tetrahydro-1-naphthalenyl)- and (2,3-dihydro-1H-inden-1-yl)-derivatives which are stated to possess affinity for alpha2 adrenoceptors, most of them being selective alpha2 adrenoceptor agonists. EP-A-0 717 037 describes 4-(1,2,3,4-tetrahydro-1-naphthalenyl)- and 4-(2,3-dihydro-1H-inden-1-yl)-1H-imidazole derivatives which possess alfa2 adrenoceptor agonistic and alpha1 adrenoceptor antagonistic activity. On the other hand, the imidazole derivatives disclosed in EP-A-0 183 492 are known as selective alpha2 adrenoceptor antagonists. Compounds acting on the said alpha adrenoceptors may exert a wide variety of peripheral and/or CNS (central nervous system) effects in mammals.
The inventors have now found that the present imidazole derivatives of the invention exhibit affinity for alpha2 adrenoceptors so that they can be useful in the treatment of various disorders or diseases wherein the alpha2 adrenoceptors are involved. Such disorders or diseases include various disorders of the central nervous system (CNS), i.e. neurological, psychiatric or cognition disorders, as well as various disorders of the pheripheric system, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.
The imidazole derivatives of the invention can be represented by the following formula (I): 
wherein
X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94, xe2x80x94Oxe2x80x94, xe2x95x90NH or xe2x80x94Sxe2x80x94;
R1 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, C3-C7-cycloalkyl, C5-C7-cycloalkenyl, C5-C7-cycloalkynyl or mono- or bicyclic aromatic or partially or fully saturated heterocyclic group with 5 to 10 ring atoms which consist of carbon atoms and one to three heteroatoms selected from N, O and S;
wherein the said phenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, C3-C7-cycloalkyl, C5-C7-cycloalkenyl, C5-C7-cycloalkynyl or mono- or bicyclic aromatic or partially or fully saturated heterocyclic group is optionally substituted with one to three substituents selected independently from halogen, xe2x80x94OH, xe2x80x94NH2, halo-C1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, OHxe2x80x94(C1-C6)-alkyl, NH2xe2x80x94(C1-C6)-alkyl and mono- or di(C1-C6-alkyl)amino;
R2 is H or C1-C6-alkyl;
R3 is H or C1-C6-alkyl; and
R4 is H or C1-C6-alkyl;
R5 is H, or R5 and R7 form together a bond;
each R6 is independently halogen, xe2x80x94OH, xe2x80x94NH2, halo-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkoxy or OHxe2x80x94(C1-C6)-alkyl;
R7 is H, OH or C1-C4-alkyl, or R7 and R5 form together a bond;
each R8 is independently OH, C1-C6-alkyl, halo-C1-C6-alkyl or C1-C6-alkoxy;
m is 0,1,2 or 3;
n is 0 or 1;
p is 0 or 1;
r is 0 or 1;
t is 0,1 or 2;
or pharmaceutically acceptable esters or salts thereof.
When X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94 and p is 0, or when X is xe2x95x90NH, 
then the bulky substituent xe2x80x94(CR2R3)rxe2x80x94 R1 is preferably at the 2- or 3-position of the 5-ring moiety (whereby, of course, in the above formulae the H-atom attached to ring carbon atom or, respectively, ring nitrogen atom will be replaced by the said substituent).
When X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94 and p is 1, 
then the bulky substituent xe2x80x94(CR2R3)rxe2x80x94R1 is preferably at the 3- or 4-position of the 6-ring moiety.
The following subgroups (1) to (17) of compounds of formula I taken alone or in any combination with each other are preferred:
1) n is 0;
2) n is 1;
3) n is 1 and R4 and R5 are H;
4) r is 0;
5) r is 1 and R2 and R3 are independently H or C1-C4-alkyl; preferably H;
6) t is 0;
7) R7 is H;
8) X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94; and p is 0 or 1;
9) X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94 and p is 0;
10) X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94 and p is 1;
11) X is xe2x80x94Oxe2x80x94;
12) R1 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, C5-C7-cycloalkyl, C5-C7-cycloalkenyl, C5-C7-cycloalkynyl, pyridyl, pyrimidinyl, thienyl, furyl, cyclohexyl, piperidyl, piperazinyl or morpholinyl; preferably R1 is phenyl, naphthyl, pyridyl, thienyl, furyl or cyclohexyl; e.g. R1 is phenyl; or e.g. R1 is cyclohexyl;
13) R1 is as defined above in subgroup (12) substituted with one to three of the substituents selected independently from halogen, xe2x80x94OH, xe2x80x94NH2, halo-C1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and C1-C6-alkoxy; preferably with one to three, e.g. one or two, of the substituents selected independently from halogen, xe2x80x94OH, C1-C6-alkoxy and C1-C6-alkyl; more preferably from F, xe2x80x94OH and C1-C6-alkoxy;
14) m is 0; or m is 1 or 2;
15) m is 1 or 2 and each R6 is independently halogen, xe2x80x94OH, C1-C6-alkoxy or C1-C6-alkyl; preferably F, xe2x80x94OH or C1-C6-alkoxy;
16) n is 0 and X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94; and/or
17) n is 1 and X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94, xe2x80x94Oxe2x80x94, xe2x95x90NH or xe2x80x94Sxe2x80x94, e.g. xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94 or xe2x80x94Oxe2x80x94.
Preferred subgroups of compounds of formula I are, for example, 
wherein R1 to R8, m, n, r and t are as defined above.
In a subgroup of the compounds of formula I, IA or IB, r is 0, or r is 1 and R2 and R3 are H. In a further subgroup of the compounds of formula I, IA or IB, n is 0, or n is 1 and R4, R5 and R7 are H. Preferably, t is 0. The optional substituent R6 is e.g. at 5- and/or 6-position of the indane ring system.
In a further preferred subgroup of the compounds I, IA or IB, R1 is phenyl, naphthyl, pyridyl, thienyl, furyl or cyclohexyl, e.g. phenyl, pyridyl or cyclohexyl, such as phenyl or cyclohexyl, e.g. phenyl, each of which is optionally substituted with one to three, e.g. one or two, of the substituents selected independently from halogen, xe2x80x94OH, xe2x80x94NH2, halo-C1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, OHxe2x80x94(C1-C6)-alkyl, NH2xe2x80x94(C1-C6)-alkyl and mono- or di(C1-C6-alkyl)amin; e.g. from halogen, xe2x80x94OH, C1-C6-alkoxy and C1-C6-alkyl; preferably from F, xe2x80x94OH and C1-C6-alkoxy.
In a further preferred subgroup of the compounds I, IA or IB m is 0, or m is 1 or 2 and each R6 is independently halogen, xe2x80x94OH or C1-C6-alkoxy.
A further subgroup of the compounds of formula I are compounds of formula IC or ID 
wherein R1 to R8, m, n, r and t are as defined above.
A further subgroup of the compounds of formula I are compounds of formula IE 
wherein R1 to R8, m, n and r are as defined above and t is 0 or 1.
Terms as employed herein have the following meanings: A halogen or halo is e.g. fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, more preferably fluorine. The term C1-C6-alkyl group as employed herein as such or as part of another group includes both straight and branched chain radicals of up to 6 carbon atoms, and preferably of 1 to 4 carbon atoms. The term C1-C6-alkoxy refers to xe2x80x94O(C1-C6-alkyl) wherein C1-C6-alkyl is as defined above. The term C2-C6-alkenyl includes both straight and branched chain radicals of up to 6 carbon atoms, preferably of 2 to 4 carbon atoms, containing double bond(s). The term C2-C6-alkynyl includes both straight and branched chain radicals of up to 6 carbon atoms, preferably of 2 to 4 carbon atoms, containing triple bond(s). The term halo- C1-C6-alkyl refers to C1-C6-alkyl radical, as defined above, that is substituted by one or more halo radicals as defined above, e.g. trifluoromethyl, difluoromethyl etc. The term C3-C7-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. C5-C7-cycloalkyl means cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopentyl or cyclohexyl. C5-C7-cycloalkenyl or C5-C7-cycloalkynyl refers to C5-C7-cycloalkyl as defined above, containing double bond(s) or, respectively, a triple bond in its ring structure. Mono- or bicyclic aromatic or partially or fully saturated heterocyclic group from 5 to 10 ring atoms, preferably from 5 to 6 ring atoms, which consists of carbon atoms and one to three, preferably one to two, heteroatoms selected from N, O and/or S, refers e.g. to pyridyl, pyrimidinyl, thienyl, furyl, piperidinyl, piperazinyl or morpholinyl, preferably to pyridyl, thienyl or furyl.
The compounds of formula I and the subgroups IA, IB, IC, ID and IE thereof, as well as the pharmaceutically acceptable esters and salts thereof, are referred to below as the compounds of the invention, unless otherwise indicated.
The compounds of the invention may have chiral carbon atom(s) in their structure. The invention includes within its scope all the possible stereoisomers of the compounds I, including geometric isomers, e.g. Z and E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers. Furthermore, the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of, for example, optical isomers, e.g. enantiomers, from the mixture thereof the conventional resolution methods, e.g. fractional crystallisation, may be used.
The compounds of the invention can form acid addition salts with both organic and inorganic acids well known in the field of pharmaceuticals. Typical acid addition salts are e.g. chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates. Furthermore, in the compounds of the invention, wherein R6, R8 and/or the optional substituent at the ring moiety as R1 is OH, the said xe2x80x94OH functionality may form esters with pharmaceutically acceptable acids which are conventional in the field of pharmaceuticals and which retain the pharmacological properties of the free form. Examples of such esters include esters of aliphatic or aromatic alcohols, e.g. lower alkyl esters, e.g. methyl, ethyl and propyl esters.
The compounds of the invention can be prepared using e.g. the following methods. Accordingly:
(a) The preparation of, for example, compounds of formula 1, wherein n is 1, may be illustrated e.g. with the following reaction scheme A: 
wherein X, R1 to R4, R6, R8, m, r and t are as defined above and Rxe2x80x2 is H or a conventional protecting group for xe2x95x90NH in the imidazole ring, e.g. benzyl, trityl (xe2x80x94CPh3) or SO2NMe2.
The step (a) is a conventional McMurry coupling reaction, i.e. a reductive carbonyl coupling of an imidazole carbaldehyde or an imidazolyl alkylketone III with a ketone II in the presence of a catalyst, e.g. titanium(0) (e.g. produced in situ), in an inert solvent, e.g. THF, at room or elevated temperature. The resulted compound of formula I, wherein R5 and R7 form together a bond (Ixe2x80x2), may be deprotected, if necessary, and isolated according to the known methods, or converted by hydrogenation of the double bond to another compound of formula I, wherein R5 and R7 are H (Ia, step b). In the hydrogenation step (b) the possible protecting group in the imidazole ring is eliminated simultaneously. The compound of formula I obtained is isolated and worked up in a manner known in the art;
(b) The preparation of, for example, compounds of formula I, wherein n is 0 and R7 is H, may be illustrated e.g. with the reaction scheme B: 
wherein X, R1 to R3, R6 and R8 m, r and t are as defined above and Rxe2x80x2 is a conventional protecting group for xe2x95x90NH in the imidazole ring, e.g. benzyl, trityl (xe2x80x94CPh3) or SO2NMe2.
In the reaction scheme B, a compound of formula II is first reacted with a compound of formula IV, in the presence of a Grignard-reagent, such as EtMgBr, in a suitable solvent, e.g. CH2Cl2, at dry reaction conditions, at room temperature or elevated temperature, and the reaction mixture obtained is then treated with an aqueous NH4Cl-solution to obtain the compound of formula V. The hydroxyl group and the amino protecting group R"" of the compound of formula V can be eliminated in a manner known in the art, e.g. using e.g. TMSCIxe2x80x94Nalxe2x80x94CH3CN, in a suitable solvent, e.g. CH2Cl2, at room or elevated temperature. In the elimination step an intermediate indene-imidazole may be formed, which is further reduced in a manner known in the art. The compound of formula I (Ib) thus obtained is isolated using conventional methods.
(c) The preparation of, for example, compounds of formula I, wherein n is 0, may further be illustrated e.g. with the following reaction scheme C: 
wherein R1 to R3, R6, R7, m and r are as defined above X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94, p is 0 or 1 and Rxe2x80x2 is a conventional protecting group for xe2x95x90NH in the imidazole ring, e.g. benzyl or trityl (xe2x80x94CPh3).
In the method of scheme C the compound IIIxe2x80x2 is reacted with Grignard reagent VI at room or elevated temperature in a suitable solvent. The resulted compound VII is cyclized in a manner known in the art to obtain the end product Ic.
The other compounds of formula I not illustrated in the above schemes can be prepared according to or analogously to the methods described above or known in the prior art, starting from the suitable starting material. As to the prior art methods reference is made e.g. to WO-A-97 12874, the contents of which are hereby incorporated by reference.
The starting compounds II are commercially available or they may be prepared via a variety of known synthetic routes using suitable starting materials and conventional methods known to those skilled in the art. For instance the compounds of formula II, wherein X is xe2x80x94CH2xe2x80x94(CH2)pxe2x80x94, p is 0 or 1, can be prepared according to or analogously to the methods described by Sommer, M. B. et al., J.Org.Chem., vol.55,1990, p.4822, Welch, W. M. et al., J.Med.Chem., vol.27,1984, p.1508, and/or Bxc3x8gesxc3x8, K. P., J.Med.Chem., vol.26, 1983, p.935, the contents of which are hereby incorporated by reference. As a further example, the preparation of compounds II can be carried out according to or analogously to the methods described in the above-mentioned WO-A-97 12874, Miller L. L. and Boyer R. F., J.Am.Chem.Soc., vol.93(3), 1971, p.650-656, or Smonou I. and Orfanopoulos M., Synthetic Communications, vol.20(9), 1990, p.1387-1397, which are also incorporated by reference herein.
As to the starting material III, IIIxe2x80x2 and IV, these are commercially available, for example, in an unprotected form, or they may be prepared according to the methods known to those skilled in the art (cf., for example, Kirk, K. L, J.Heterocycl.Chem., vol.22,1985, 57). If necessary, the xe2x95x90NH of the imidazole can be protected using conventional methods and protecting groups (Rxe2x80x2), e.g. benzyl or trityl. It is understood that, due to the tautomerism, the protecting group Rxe2x80x2 may be attached to either of the two nitrogen atoms of the imidazole ring.
If necessary, also R6, R8 and/or the optional substituent at the ring moiety as R1 can be protected in a manner known in the art. Such protecting groups as well as the optional protecting group Rxe2x80x2 can be removed at the final stage using suitable conventional deprotection method(s) known in the art.
It should be noted that the above disclosed synthetic routes are meant to illustrate the preparation of the compounds of the invention and the preparation is by no means limited thereto, i.e. other synthetic processes which are within the general knowledge of a skilled person are also possible.
The compounds of the invention may be converted, if desired, into their pharmaceutically acceptable salt or ester form using methods well known in the art.
As already mentioned hereinbefore, the compounds of the invention show interesting pharmacological properties, namely they exhibit affinity for alpha2 adrenoceptors. The said activity of the compounds of the invention is demonstrated with the pharmacological test presented below.
Antagonist activity on alpha2 Adrenoceptors (Alpha2AR) in rat vas deferens in vitro
Rats were killed by CO2-suffocation. Vas deferentia were dissected out and both prostatic halves were removed to tissue chambers containing Krebs-solution of the following composition (mM): NaCl 118, KCl 4.7, CaCl22.5, KH2PO41.2, MgSO40.6, NaHCO325, glucose 11.1, aerated by 5% carbogen, temperature 37xc2x0 C., pH 7.4. Propranolol 260 g/l and desipramine 2 g/ml were added to prevent the possible effects on alpha-adrenergic receptors and to prevent re-uptake of released norepinephrine, respectively. Preparations were tied to the bottom hooks of the incubation chambers and then to isometric force-displacement transducers above. Electrical stimulation was started after the equilibrium period (5 minutes under a resting tension of 0.5 g) by introducing field stimulation with the following parameters: twin-pulses, voltage 70 V, frequency 0.2 Hz, delay 5 ms, duration 2 ms. As soon as the electrically induced twitch response was stabilised, the test compounds were administered by a cumulative fashion with half logarithmic increments at five minute intervals. Inhibition of the electrically evoked contractions was measured as the response to alpha2AR agonists. Antagonist was administered into the incubation medium at least five minutes before agonist. Means xc2x1 SEM of percentage inhibition were calculated in the absence and in the presence of antagonist and expressed as dose-response curves. In order to express the antagonist potency, the pA2-value was calculated. The results of the test are reported in Table 1.
In general, the compounds of the invention exhibiting alpha2-antagonistic activity may be useful for therapeutical indications in which alpha2-antagonists are used. They may also be used for reversal of the effects of alpha2-agonists.
Accordingly, the compounds of the invention may be useful, for example, in the treatment of different neurological, psychiatric and cognition disorders. Furthermore, they may be used in the treatment of various peripheral disorders, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.
The compounds of the invention may be administered enterally, topically or parenterally.
The compounds of the invention may be formulated alone or together with another active ingredient and/or together with a pharmaceutically acceptable diluent, carrier and/or excipient in different pharmaceutical unit dosage forms, e.g. tablets, capsules, solutions, emulsions and powders etc., depending on the route of administration, using conventional techniques. The pharmaceutically acceptable diluent, carrier and/or excipient can be selected from those conventionally used in the field of pharmaceuticals noticing the chosen route of administration.
The amount of the active ingredient varies from 0.01 to 75 weight-% depending on, for example, the type of the dosage form.
The specific dose level of the compounds of the invention depends on several factors such as the compound to be administered, the species, age and the sex of the subject to be treated, the condition to be treated and on the route and method of administration. Accordingly, the dosage for parenteral administration is typically from 0.5 xcexcg/kg to 10 mg/kg per day and that for oral administration is from 5 xcexcg/kg to 100 mg/kg for an adult male.
The present invention also provides a compound of the invention or an ester or salt thereof for use in a method of treatment of human or animal body.
The present invention further provides a compound of the invention or an ester or salt thereof for use in the treatment of different CNS-disorders, such as neurological, psychiatric and cognition disorders, or in the treatment of various peripheral disorders, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.
The invention also provides the use of a compound of the invention or an ester or salt thereof in the manufacture of a medicament for the treatment of different CNS-disorders, e.g. neurological, psychiatric and cognition disorders, or in the treatment of various peripheral disorders, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.
The invention further relates to a method for the treatment of different CNS-disorders, e.g. neurological, psychiatric and cognition disorders, or peripheral disorders, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction, by administering to a subject in need of such treatment an effective amount of the compound of the invention or a pharmaceutically acceptable ester or salt thereof.
The present invention will be explained in more detail by the following examples. The examples are meant only for illustrating purposes and do not limit the scope of the invention which is defined in claims.